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Combined stem cell transplantation and targeted microstimulation to direct the fo

联合干细胞移植和定向微刺激来指导

基本信息

批准号：
8288742
负责人：
Philip J Horner
金额：
$ 30.32万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-15 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8288742
关键词：
Address Adult Age Anatomy Animal Model Astrocytes Autologous Axon Behavior Behavioral Brain Bypass CNS degeneration Cell Therapy Cell Transplants Cells Central Nervous System Degenerative Diseases Central Nervous System Diseases Cervical spinal cord injury Chondroitin Sulfate Proteoglycan Cicatrix Clinical Corticospinal Tracts Development Devices Electric Stimulation Electronics Elements Embryo Environment Felis catus Fire - disasters Goals Growth Healed Implant Individual Inflammatory Response Injury Intervention Intrinsic drive Lead Lesion Literature Location Measures Methods Molecular Chaperones Motor Cortex Natural regeneration Nerve Fibers Nerve Regeneration Nervous System Trauma Nervous system structure Neuraxis Neurites Neuroglia Neuronal Plasticity Neurons Oligodendroglia Pathway interactions Patients Peripheral Peripheral Nerves Phenotype Plastics Production Pyramidal Tracts Recovery Recovery of Function Reporting Research Rodent Model Sensory Shapes Signal Transduction Site Societies Spinal Spinal Cord Spinal Cord Lesions Spinal cord injury Staging Stem cell transplant Stem cells Stroke Synapses Synaptic plasticity Testing Time Tissues Transplantation Traumatic Brain Injury adult stem cell axon growth axon guidance axon regeneration axonal sprouting central nervous system injury effective therapy electrical microstimulation flexibility functional restoration healing improved injured microstimulation neonate nerve stem cell nervous system development nervous system disorder neuronal survival neurotrophic factor nonhuman primate novel novel strategies regenerative reinnervation relating to nervous system repaired stem cell therapy success white matter

项目摘要

DESCRIPTION (provided by applicant): The goal of this research is to develop and test a method to guide repair and regeneration of the central nervous system following injury or degeneration. We propose that by creating both a regenerative environment as well as directing intrinsic plasticity among neurons, we can achieve a new milestone in neural repair. If successful, this approach could be used to treat patients suffering from central nervous system damage such as traumatic brain injury, stroke, or spinal cord injury in order to reduce the burden of neurological disease on individuals and society. Our studies employ a novel combination of targeted electrical microstimulation and stem cell therapies to guide the formation of appropriate and functional connections bypassing an injury. We will test our approach in a rodent model of incomplete cervical spinal cord injury that is representative of insults throughout the central nervous system. It is known that during development of the nervous system, stem cells produce immature astrocytes that create an environment to support axon guidance and synaptic plasticity. Here, we hypothesize that neural plasticity and the repair of damaged neurons can be facilitated by re-creating the developmental phenotype of astrocytes surrounding an injury site. In a first of its kind approach, we will derive immature astrocytes from autologous adult stem cells and transplant them near a spinal cord lesion to create a supportive environment for plasticity and neural repair. We propose that providing environmental support alone has had limited success because it does not address the intrinsic drive of neurons to grow. Synchronous and appropriate neural activity is also needed to direct the formation of functional synaptic connections in the intact and injured nervous system. Here we will use a neuroprosthetic device to deliver microstimulation to targeted sites within the spinal cord below the injury that is synchronized with functionally related activity in the motor cortex. Targeted microstimulation will strengthen appropriate and functional connections via mechanisms of Hebbian plasticity. Rather than attempt long-tract regeneration in the spinal cord, our approach aims to promote the formation of indirect connections via spared pathways bypassing the lesion. The extent of recovery will be measured using behavioral tasks, and electrophysiological and histological methods. This will determine the ability of synchronous, targeted microstimulation to guide implanted stem cells in the formation of appropriate and functional connections following damage to the central nervous system. We contend that microstimulation will collaborate with the transplant environment to produce a multiplicative effect on local plasticity.

描述（由申请人提供）：本研究的目的是开发和测试一种方法，以指导损伤或变性后中枢神经系统的修复和再生。我们认为，通过创造一个再生环境以及指导神经元之间的内在可塑性，我们可以实现神经修复的新里程碑。如果成功，这种方法可以用于治疗患有中枢神经系统损伤的患者，如创伤性脑损伤，中风或脊髓损伤，以减轻神经系统疾病对个人和社会的负担。我们的研究采用了一种新的靶向电微刺激和干细胞疗法的组合，以引导绕过损伤的适当和功能性连接的形成。我们将在代表整个中枢神经系统损伤的不完全颈脊髓损伤的啮齿动物模型中测试我们的方法。已知在神经系统发育期间，干细胞产生未成熟的星形胶质细胞，其创造支持轴突引导和突触可塑性的环境。在这里，我们假设，神经可塑性和受损神经元的修复可以通过重建损伤部位周围星形胶质细胞的发育表型来促进。在第一种方法中，我们将从自体成体干细胞中获得未成熟的星形胶质细胞，并将其移植到脊髓病变附近，为可塑性和神经修复创造支持性环境。我们认为，单独提供环境支持的成功有限，因为它没有解决神经元生长的内在驱动力。在完整和受损的神经系统中，还需要同步和适当的神经活动来指导功能性突触连接的形成。在这里，我们将使用一种神经假体装置，将微刺激传递到损伤下方脊髓内的目标部位，与运动皮层中的功能相关活动同步。有针对性的微刺激将通过赫布可塑性机制加强适当的和功能性的连接。我们的方法不是试图在脊髓中进行长束再生，而是旨在通过绕过病变的备用通路促进间接连接的形成。恢复程度将使用行为任务以及电生理和组织学方法来测量。这将确定同步的、有针对性的微刺激引导植入的干细胞在中枢神经系统损伤后形成适当的功能性连接的能力。我们认为，微刺激将与移植环境合作，对局部可塑性产生倍增效应。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Caudalized human iPSC-derived neural progenitor cells produce neurons and glia but fail to restore function in an early chronic spinal cord injury model.

尾部化的人 iPSC 衍生的神经祖细胞产生神经元和神经胶质细胞，但无法恢复早期慢性脊髓损伤模型中的功能。

DOI：
10.1016/j.expneurol.2013.07.010
发表时间：
2013-10
期刊：
EXPERIMENTAL NEUROLOGY
影响因子：
5.3
作者：
Nutt, Samuel E.;Chang, Eun-Ah;Suhr, Steven T.;Schlosser, Laura O.;Mondello, Sarah E.;Moritz, Chet T.;Cibelli, Jose B.;Horner, Philip J.
通讯作者：
Horner, Philip J.

Affective Brain-Computer Interfaces As Enabling Technology for Responsive Psychiatric Stimulation.

情感脑机接口作为响应性精神刺激的支持技术。